title: The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.
abstract: Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ingrid P
authors.initials: IP
authors.lastname: Vogelaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marjolijn J
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Rapkins
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: Program for Clinical Cancer Genetics, Departments of Medicine (Oncology) and Genetics, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Nicolette
authors.initials: N
authors.lastname: Chun
authors.affiliation: Program for Clinical Cancer Genetics, Departments of Medicine (Oncology) and Genetics, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Gastrointestinal Cancer Prevention Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Ladabaum
authors.affiliation: Department of Medicine and Familial Cancer Program, Vermont Cancer Centre, University of Vermont, Burlington, VT, USA.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: McKinnon
authors.affiliation: Department of Medicine and Familial Cancer Program, Vermont Cancer Centre, University of Vermont, Burlington, VT, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Greenblatt
authors.affiliation: 1] Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia [2] Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hitchins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D044465:White People / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1